Europe Invests in HIV Vaccine Research

Talent-rich but comparatively resource-poor and under intense political pressure, the European Union launches a pair of research initiatives under a €45 million umbrella.

By Michael Dumiak

The headlines from Europe this summer paint a picture of a grim and inward-looking place: a continuing struggle to cope with an unprecedented immigration and integration crisis and the United Kingdom’s vote to leave the European Union (EU).

The EU, however, is also working to keep its focus on long-term issues in public health, specifically the pursuit of an HIV vaccine. Earlier this year the European Commission launched a pair of research initiatives backed by €45 million (approximately US$55 million) aiming to produce, compare, evaluate, and test early development-stage HIV vaccine candidates. This is a relatively modest amount: the annual US spending on HIV vaccine research is about $836 million, with $595 million of that from the public sector, according to the Resource Tracking for HIV Prevention Research and Development Working Group’s 2015 report.

But Europe has many top-flight labs with talented research teams scattered across the continent that consistently make meaningful contributions to basic HIV research, including efforts to develop a vaccine and a cure. The European Commission’s most recent funding initiative supports two projects: The European AIDS Vaccine Initiative (EAVI2020) and the European HIV Vaccine Alliance (EHVA). The Brussels-based European Commission intends the initiative to encourage collaboration and discovery, bringing together dozens of institutions to develop tools to sort and predict the behavior of vaccine candidates, speed the testing process, and contribute to the global effort to expedite the development of an HIV vaccine.

The two five-year projects are meant to be part of a developing portfolio of research projects that the European Commission is building through its Horizon 2020 program. As Brussels continues to try to bridge the fissures besetting the EU, its scientific efforts are attracting higher visibility as a measure of its ability to function. But the HIV researchers involved in EAVI2020 and EHVA are used to high stakes.

The Global HIV Vaccine Enterprise recently partnered with IAVI Report to discuss these new projects with four of the key figures involved: Ruxandra Draghia-Akli, director of the Health Directorate at the European Commission’s Research and Innovation Directorate General; Yves Lévy, chief executive officer (CEO) of the French Institute of Health and Medical Research (INSERM) and coordinator of the EHVA; Giuseppe Pantaleo, chief of the Service of Immunology and Allergy at Lausanne University Hospital, executive director of the Swiss Vaccine Research Institute, and co-scientific coordinator of EHVA; and Robin Shattock, mucosal infection and immunity professor at Imperial College London and the coordinator of EAVI2020.

RUXANDRA DRAGHIA-AKLI

How do you believe the multi-disciplinary nature of EHVA and EAVI2020 will accelerate vaccine development?

The nature of HIV has posed an enormous challenge to the research community that has made endless efforts to develop an effective vaccine and put an end to the AIDS epidemic. There are several bottlenecks which prevent the identification of viable candidate vaccines at an early stage of the development process. These are challenges that no single discipline or research group alone can address. This is a long process and successful vaccine research and development builds on collaborative work, frequently at a global level. It is within this landscape that the EU, with its funding program for research and innovation, Horizon 2020, has invested €45 million in 2015 to support two large and complementary consortia: EHVA and EAVI2020. In these partnerships, European scientists will work together, and in collaboration with researchers from outside Europe, to successfully develop predictive tools and select the most promising vaccine candidates to be tested at an early stage of the process.

With their collaborative structures, the consortia pulled together the necessary critical mass of expertise and complementary skills needed to tackle difficult research challenges—each group bringing its valuable expertise and perspective. In addition, as I believe competition does not prevent collaboration, by funding both consortia the Commission also enhanced the competitive environment in this field which can function as an extra push in accelerating the development of new vaccine candidates.

Therefore, with EHVA and EAVI2020, we offer a triple win: we promote European scientific excellence and global collaborations, accelerate the development of novel prophylactic and therapeutic vaccine candidates, and enhance European competitiveness.

What challenges do you anticipate with the collaborative structure?

Collaboration across disciplines, sectors, and countries can be challenging because of technical, operational, and cultural barriers. However, Europe has a long history of supporting collaborative research, starting with its first framework program for research launched in 1984. The EU funding programs, which are open to the world, have allowed scientists to collaborate together in a joint effort to explore, understand, and provide solutions for the health of patients, including the development of an HIV vaccine. Nowadays, most of the academic researchers receiving our grants are used to working together in a multi-disciplinary environment and in teams with civil society, patient organizations, the pharmaceutical industry, and subject matter experts.

What lessons from previous multi- and cross-disciplinary strategic approaches might help guide the EHVA and EAVI2020 collaborative efforts?

For almost thirty years the European Commission has supported multi- and cross-disciplinary consortia. This was done under the cooperation pillar of the framework programs for research and innovation, and continues under the Horizon 2020 societal challenge “Health, demographic change and well-being,” in the public-private partnership Innovative Medicines Initiative (IMI), and the European and Developing Countries Clinical Trials Partnership (EDCTP). The lessons learned from the previous approaches are that to address complex scientific challenges one needs more than the excellence of a single group. What is needed is a well-balanced partnership that includes a broad range of expertise from different disciplines and different types of organizations, ranging from academia to private (small, medium, and large) companies, patient groups, and regulatory bodies, each bringing its own perspective and an open mind to working with others. The investigators in EHVA and EAVI2020 are accustomed to this, as many of them have worked in different partnerships in previous consortia, such as the CUT’HIVAC and IDEA projects, which were successful in advancing the vaccine field.

Does a framework currently exist to maximize knowledge sharing and synergies among the collaborators, including with partners in industry?

Knowledge sharing and synergies are an integral part of our funded collaborative research. A part of all EU-funded grants is dedicated to dissemination, communication, and exploitation of the results and knowledge generated, and this includes information exchange with external stakeholders. Following Horizon 2020’s open access policy, our grantees must ensure that peer-reviewed scientific publications are deposited in repositories and made open access. Also, a novelty in Horizon 2020 to which EHVA and EAVI2020 can apply on a voluntary basis is the Open Research Data Pilot, which aims to improve and maximize access to and re-use of data generated by the projects. In addition, the European Commission, which directly manages and monitors the grants, plays an active role to facilitate this process and maximize the synergies among collaborators. For instance, we regularly organize workshops and other meetings around scientific- or policy-oriented themes where representatives from different consortia and organizations are encouraged to work together. And I believe that the Global HIV Vaccine Enterprise, which brings together the main groups working on HIV vaccines and which the European Commission has been a member of since its inception, has a role to play in this regard.

EHVA and EAVI2020 have nine partners in common, including IAVI, which among other roles is responsible for the implementation of the dissemination plan. The two consortia also have links with projects funded under the Innovative Medicines Initiative, the largest public-private partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA) that brings together relevant stakeholders to drive the development of better and safer medicines and other interventions in an open innovation ecosystem. I trust that all these elements together will ensure a productive environment among the collaborators for sharing the knowledge generated, further strengthening the synergies, and helping establish new collaborations.

How can EHVA and EAVI2020 best build meaningful capacity—specifically, in sub Saharan Africa—for sustainable development, such as establishing long-term translational research programs?

In 2003 the European Commission together with several European member states and sub-Saharan Africa countries established the EDCTP. This was an important step towards the creation of a long-term and sustainable partnership to fight the three main poverty related diseases: HIV/AIDS, tuberculosis, and malaria. Based on its successes in 2014 we have renewed, reinforced, and extended this partnership with the second phase of EDCTP, which has a broader scope, including the engagement with other international funders. EDCTP2 has now become one of the crucial facilitators in capacity building and accelerating the clinical development of new or unproven products against these diseases, including HIV vaccines. Therefore, when we opened the call for proposals for HIV vaccine development, we specifically requested the applicants establish close links with EDCTP2. Both EHVA and EAVI2020 have included several investigators which have been working with EDCTP2, thus ensuring that the promising vaccine candidates generated during the implementation of the program will be proposed to EDCTP2 for advancement in clinical development.

The interview with Ruxandra Draghia-Akli was conducted by the Global HIV Vaccine Enterprise.

YVES LÉVY AND GIUSEPPE PANTALEO

How will EHVA integrate a multidisciplinary approach to address challenges in HIV vaccine research?

YL: EHVA brings together 39 partners from Europe, Africa, and the US across a very diverse set of disciplines in discovery research and product development. The alliance includes expertise in the fields of molecular and structural biology, vector design, adjuvant delivery, immunology, clinical research, and biostatistics. The aim for this team is to develop an efficient platform for developing, evaluating, and selecting prophylactic and therapeutic HIV vaccines. Core components in the Alliance are the immune profiling and data management platforms to rank novel and existing vaccine candidates and ensure efficient selection of candidates during pre-clinical and clinical development.

What are the components of the platform that the EHVA will use to develop prophylactic and therapeutic vaccine candidates?

YL: The Multidisciplinary Vaccine Platform (MVP) comprises four components: discovery, immune profiling, data integration and down-selection, and clinical trials. Each brings together relevant expertise within the field. The discovery arm will generate immunogens able to induce potent non-neutralizing and neutralizing-antibody responses and T-cell responses. The immune profiling arm will standardize a set of assays and rank the novel vaccine candidates against existing ones. It will also continue to develop novel assays to further enhance this process. The data integration arm will develop statistical tools to interpret the data generated and build a data warehouse system for hosting the preclinical and clinical datasets. And the clinical trials arm will conduct Phase I trials to inform candidate selection and support prediction of success and failure in early stage research. This serves not only as a platform for selecting candidates developed within EHVA, but can also serve the vaccine field beyond the EHVA project lifespan.

Can you explain a bit more about the immune profiling?

GP: Immune profiling identifies the uniqueness of the phenotypic and functional properties of the immune response elicited by the vaccine under development. A variable number of methodologies are used to profile the vaccine-induced immune response qualitatively and quantitatively. The availability of validated assays is critical in profiling the immune response. The immune profiling platform includes a set of 28 assays encompassing humoral, cellular, and innate immunity including the set of six assays measuring the immune correlates of efficacy identified in the RV144 trial. The immune profiling platform will be instrumental for ranking the different vaccines under investigation, the down-selection of the best-in-class vaccine candidate based on pre-established criteria, and the cross-comparison with other vaccines developed in other programs.

How will the EHVA build on the results of RV144, the only trial so far to show any efficacy?

YL: EHVA builds on the learnings from the RV144 trial by developing tools to help identify the correlates of immunity, optimize vaccine regimens, and aid the selection of novel vaccine candidates for further development. The aim is to develop prophylactic HIV vaccine candidates that generate more durable and potent immune responses. To this end, EHVA is building on technologies and insights generated in the field and will focus on the development of RNA-based vaccine candidates, novel protein candidates, novel delivery system and adjuvants, as well as head-to-head comparisons of different vaccine regimens already developed by partners in the Alliance to optimize them. EHVA will also focus on developing therapeutic vaccine candidates and help elucidate mechanisms for a functional cure.

What novel vaccine candidates are you prioritizing?

GP: EHVA will aim to bring one RNA-based vaccine candidate and one protein based vaccine candidate to early phase clinical testing within the grant’s five-year timespan. The primary goal of these new vaccine candidates is to elicit antibody responses directed against vulnerable sites of HIV Env. The combined used of the novel vector with protein-based vaccines will hopefully also induce durable antibody responses that are necessary for long-term protection. These novel vaccine combinations will be compared head-to-head with a number of benchmark candidates that have already been in clinical development thus representing another unique strength of the EHVA program.*

*These benchmark candidates include two DNA vaccines: the EuroVacc DNA Env/Gag/Pol vaccine and the GTU DNA vaccine developed by Finnish biotech FIT in Helsinki. There are also two poxvirus-based vaccines that have undergone previous testing: the NYVAC Env/gag/pol and the Inserm-ANRS MVA-HIV-B vaccine. For more information go to clinicaltrials.gov.

YL: Several RNA-based vaccine candidates will be compared in preclinical studies including replicon RNA, replicon RNA delivered as naked DNA, and messenger RNA. The modified HIV Envelope proteins that will be developed and compared include stabilized existing Env trimers and trimers with added glycans to silence immunodominant, non-neutralizing surfaces of the viral spike. The improved envelope trimers will be coupled with virus-like particle (VLP) or dendritic cell (DC)-targeting delivery systems.

Those that perform best in preclinical studies (small animals and nonhuman primates) will be selected for clinical trials and evaluated in a prime-boost combination to develop regimens with improved antibody and T-cell responses. Other approaches, including VSV [vesicular stomatitis virus] vectors and adjuvants will be more upstream and part of the discovery track.

GP: There are also a number of new adjuvants that are going to be evaluated. Right now there are only three adjuvants that are approved for clinical use by the US Food and Drug Administration (FDA). It’s a very difficult field because there are major regulatory issues in bringing a new adjuvant into clinical development. Within the scope of our program, our work is going to focus predominantly on the pre-clinical evaluation of new adjuvant preparations that are similar, but not identical, to those that are approved by the FDA.

What does EHVA anticipate will be the collateral benefits of this approach?

YL: We plan to deliver an immune profiling platform and a central data analysis platform with state-of-the-art statistical tools for the analysis and interpretation of complex data and algorithms for the effective selection of vaccines. The field will be able to benefit from these tools to better predict poor or low efficacy of a candidate early in the process. This can also provide value for other vaccine efforts. Furthermore, the support from the European Commission and Swiss Government to develop vaccines against HIV/AIDS and other global health threats, we hope, will send a positive signal to the EU member states and other international funders about the importance of supporting these efforts.

How does EHVA seek to build meaningful capacity, specifically in sub-Saharan Africa?

YL: EHVA includes partners from Uganda, Tanzania, Mozambique, and Côte d’Ivoire. They bring extensive expertise and robust capacity for AIDS vaccine R&D to the Alliance, and will help provide further training for African researchers. Furthermore, we liaise closely with the European and Developing Countries Clinical Trials Partnership (EDCTP) to help ensure that sufficient capacity is available for the further development of HIV vaccine candidates that are generated by EHVA. It is anticipated that any promising vaccine candidates, prophylactic or therapeutic, that warrant further development in larger scale clinical trials will be supported by the EDCTP.

The interviews with Yves Levy and Giuseppe Pantaleo are based on conversations with IAVI Report and the Global HIV Vaccine Enterprise.

ROBIN SHATTOCK

Is this program meant to supplement other HIV research initiatives or is it a singular effort?

It is funded as a one-off, standalone piece. We are encouraged to use these resources to leverage further collaborations and potentially further funding. We’re very much integrated into a wider international program, but we are making sure that we’re not duplicating work done by the CHAVI-IDs [Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery grants] in the US. We are closely linked to the CAVD [The Collaboration for AIDS Vaccine Discovery] and we have representation on our advisory board from the US National Institutes of Health. We’ve taken great effort to make sure this isn’t a me-too approach where we are all building similar versions of the same space rocket. We have tried to make sure that we’re working in a unique space so that we can provide a unique contribution to the field.

What kind of infrastructure is in place? What’s needed?

There are 23 partners across Europe, all with very different but complementary skill sets. We took to heart the original challenge that was put out by the European Commission, which was to try and generate 10 new vaccine candidates and put them into the clinic within five years. That’s ambitious. We made a deliberate policy that we would not work on any existing candidates that were already in the field, and I think this is one of the things that makes us a little more unique. We have tasked ourselves to get eight new, next-generation, stabilized, native-like trimers and two novel T-cell vaccine approaches into the clinic within that five-year time period.

What can you tell us about the different candidates?

For the B-cell candidates, we are building on what came out of the very elegant work John Moore and Rogier Sanders did that led to the development of the BG505 SOSIP immunogen.*

*The BG505 SOSIP is a stabilized trimeric HIV Env protein. John Moore of the Cornell Medical College and Rogier Sanders of the University of Amsterdam did pioneering work in creating BG505 SOSIP and testing it in animal studies as an antibody-producing immunogen (see Research Brief, IAVI Report, Vol. 19, No. 2, 2015.

As a consortium we are working to improve the breadth of the antibody response. We are trying to induce breadth by looking at conserved and mosaic immunogen approaches in collaboration with Bette Korber from the US. Rogier Sanders and the consortium are also using viral isolates derived from HIV-infected volunteers that developed broad neutralizing responses to the virus within the first six months or so (rather than one to two years) and using these as a road map for driving B-cell responses toward neutralizing breadth. Our intention is to select a series of B-cell immunogens with potential to do the same in non-infected subjects over a short period of time. Essentially, we are looking to develop approaches that have translational potential in a real-world setting.

Then we will move immunogens that have been shown to induce quite a good level of breadth from pre-clinical study to early clinical/experimental medicine Phase I trials, and try to do it quickly. A significant part of our focus is to be in humans as fast as possible so that we can get an early readout on human immunogenicity. Understanding how to engage the right B cells in humans, and particularly germline B cells, will be critical to solving this problem. We’re not anticipating that these first shots at goal will be a score, but they will help us get better at predicting what makes a good immunogen and how to focus the immune response towards making broadly neutralizing antibodies.

In parallel to our dash to the clinic, we have a slower, considered, iterative, rational design where human immunogenicity will feed back into the design in the earlier stages. The goal is that by the end of the program we will have built up a really extensive experience with B-cell immune responses in humans that will generate a further generation of immunogens that will be ready to go and significantly better than anything we can design right now. That’s the ambition.

How will you be able to begin clinical trials so quickly?

All of these candidates will be tested in nonhuman primate studies. Some of the early primate studies will be what we call a para-clinical approach—we will test the same immunogens in macaques alongside humans to be able to understand the utility of macaques in predicting useful antibody responses.

We are already comparing the B-cell response to immunization across rhesus macaques and cynomolgus macaques to see which of those two models best fits our purpose. We also have a collaboration with Kymab, which has a mouse model that expresses the human immunoglobulin repertoire. We’ll look at that as well with the same immunogens. We will then have a really clear picture of how predictive these models are, where they are useful in terms of prediction, and where they may be misleading. A second aim or second challenge is to reduce the risk of late-stage failure by improving the predictive utility of what is taken into larger clinical trials. That’s our intention.

What other paths are you pursuing?

We have a parallel track looking at novel T-cell immunogens. There we have two main groups driving two different concepts. The first one is from Tomas Hanke and Andrew McMichael at Oxford, who have been working on developing what they call a conserved mosaic immunogen design. These immunogens are based on computational algorithms, again developed by Bette Korber, that select all the conserved parts of the virus. These immunogens have been put into a range of nucleic acid and viral vectors to move into clinical trials, and earlier versions have already shown a greater breadth of T-cell recognition, which looks quite promising. We are partnering with IAVI, which is funding some of the manufacturing costs, and we’re hoping that additional partners may come in to support that part of the project.

The other group is led by Christian Brander from Barcelona, and his approach is similar but different. He’s selected conserved epitopes that have shown beneficial control in HIV-infected individuals. Our expectation is that they will do the same in healthy volunteers and infected subjects that have not mounted similar responses.

We’re going to compare those two approaches side by side in clinical trials to see what strengths or weaknesses they have. In the past, the field’s really just focused on magnitude of T-cell response and hasn’t really grappled with the issue that greater breadth may be much more important in constraining viral replication.

Outside of the very promising data that Louis Picker has with his rhesus CMV [cytomegalovirus] approach, we think these two are probably the best two T-cell strategies that can be taken into humans within the timeframe that we have.

It’s refreshing to hear about some European initiatives. How would you describe the status of HIV vaccine research in Europe overall?

I would say there’s a lot of talent but a lot less funding. That means we have to be smarter about what we do. We think quite carefully before we move into an area, and I think that the less money you have, often the more creative you have to be in order to make an impact. Obviously, one doesn’t want to talk oneself out of funding. It’s good to have. It certainly is daunting in terms of trying to be competitive against some of these very large networks in the US.

But to kind of offset that, rather than trying to compete, where possible we’re trying to collaborate and be partners. If we collaborate, we can really add to the field, and I think that’s the way to be most successful. In Europe, I think people are definitely likely to take risks and I think there’s perhaps more diversity in approach at the very early level. But because there’s less funding, many of these concepts don’t get very far, even though they may have some merit. Still, nothing’s done in isolation. A lot of the investigators in Europe are also funded by international organizations and involved in other international consortia.

How are you managing the ambitious plans for EAVI2020?

We’ve got really a very well mapped-out plan, and because of the ambitious scope our milestones and our planning is really very tight. We’re monitoring on a weekly basis where we are in the program and constantly reviewing the timelines to make sure that everything is in place. When you talk about trying to move products into humans, everything that could go wrong usually does go wrong and timelines always slip. We’re having to make decisions now about things that will be tested in humans in three or four years’ time. If any of those decisions are delayed it will start to push the trials off past the end of the program, so we can’t afford any slack.

Michael Dumiak reports on global science, technology, and public health and is based in Berlin.